Amphetamines are among the most widely used illicit drugs worldwide and in the U.S. The Department of Veterans Affairs spends annually $15 million for treatment of acute hospitalization for methamphetamine dependence alone and approximately 11% of Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF) veterans are estimated to have used methamphetamine over the past year. Amphetamine use disorder (AUD) is an emerging problem among OEF/OIF veterans that may have significant impact on long-term functioning. Decision-making is an important function of daily life and is among the central dysfunctional behaviors in individuals with drug use problems. However, many decisions in general and decisions involving drug taking occur in a particular feeling state. Interoception comprises the neural process that underlies "how we feel" and "how we relate to others" and plays a critical role in drug-taking behavior. The insula cortex, the brain structure underlying interoceptive processing, has recently been implicated in ones ability to abstain from using drugs. A central characteristic of addictive behaviors is their relapsing nature. Several investigators have proposed that triggering aversive internal states in response to conditioned stimuli is part of the relapse process. We have some evidence that brain imaging can predict who among treatment seeking AUD individuals will relapse. Thus, by studying the behavioral and brain processes underlying decision-making and interoception in AUD individuals we can understand the neural processes underlying an individual's ability to abstain. In this proposal, two experimental approaches: (1) behavioral assessment of interoception and decision-making and (2) functional magnetic resonance imaging (fMRI) will be used to examine how amphetamine use alters behavioral and brain functioning in OEF/OIF veterans and whether these results can be used practically to predict relapse. We test the basic hypothesis that amphetamine abuse sensitizes brain structures that process the anticipation or experience of aversive emotional events and reduces the brain's ability to modulate decision-making behavior. We propose to study n=100 AUD OEF/OIF veterans and n=50 alcohol and PTSD-symptom severity matched comparison group using pleasant/aversive interoceptive stimulation to examine the reactivity of the interoceptive system and to determine the interaction between interoception and the degree to which decision-making changes as a function of errors ("how we choose after making a mistake"). The study will be focused on three specific aims: (1) to determine the subjective and behavioral effects of anticipating or experiencing an aversive or pleasant interoceptive stimulus and its impact on decision making in OEF/OIF veterans with and without AUD;(2) to determine brain activation differences during anticipating and experiencing an aversive or pleasant interoceptive stimulus and the impact on brain activation during decision making in OEF/OIF veterans with and without AUD;and (3) to determine whether behavioral or brain activation differences in OEF/OIF veterans with AUD can be used to predict severity of use - including relapse - at 1 year follow-up. The combined approach of behavioral assessment of interoception and decision-making with fMRI will be used to delineate the behavioral and neural processes in AUD individuals, which is the basis for understanding the pathophysiology of this complex disorder. The behavioral and brain imaging results will be examined for their utility as clinical tests, e.g. positive and negative likelihood ratio will be computed to determine their potential as a clinical tool to predict relapse of drug use. Ultimately, we aim to obtain a measure that can be used to predict outcomes and to use this measure in OEF/OIF veterans with AUD to develop specific interventions for high-risk patients. PUBLIC HEALTH RELEVANCE: Amphetamine use occurs in about 11% of Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF) veterans. However, the effects of this use on the brain are not well understood and it is not clear who will develop a prolonged course of addiction. This application utilizes two behavioral techniques, measuring decision-making and interoception (sensation originating from the body), and functional brain imaging to address the basic question "does amphetamine use contribute to poor functioning in OEF/OIF veterans by sensitizing individuals to negative emotions and paralyzing the individual's ability to adjust to aversive events?" The goal of this proposal is twofold: (1) to better understand the neurobiology of how amphetamine affects the brain and (2) to determine whether one can use functional brain imaging as a tool to predict who is at greatest risk for relapse in order to provide better prevention tools.